We propose to conduct the first comprehensive analysis of the determinants of normal human cognitive aging using a systems genetics resource?the Diversity Outbred panel of mice, DO?specifically designed to model the genetic and phenotypic variation of human populations. The goal of this project is to identify genetic factors and mechanisms underlying variation in normal cognitive aging, and that lead to pathologic brain aging. Large- scale human genetics studies have been central to understanding links between an individual?s genetic make- up and their risk for developing cognitive decline and Alzheimer?s Disease (AD). However, discovery of specific factors in humans has been impeded by the lack of longitudinal measures of cognitive function, heterogeneity of cognitive and neurophysiological changes, numerous environmental confounds, and difficulty obtaining molecular data at the early asymptomatic stages of disease. While mouse models offer significant experimental control for longitudinal and cross-sectional aging studies, conventional inbred strains do not recapitulate the genetic diversity necessary to identify human disease?relevant candidate genes. This proposal attempts to surmount these limitations by testing the translational relevance of gene candidates discovered using our DO panel against data from human cohorts. Since age and genetics are the leading risk factors for AD, we hypothesize that genetic factors underlying variation in normal cognitive aging (ranging from extreme risk to resilience) are involved in the development of cognitive symptoms in AD. We will take a systems genetic approach to identify genes and potential molecular and cellular mechanisms that modify the age at onset and severity of cognitive aging in a cohort of male and female DO mice (Aim 1). Candidate genes and networks will be tested for associations against normal aging and AD cohorts in humans to identify resilience factors conserved in humans (Aim 2). We will test the role of these candidate genes predicted to promote healthy brain aging (resilience), as well as those associated with a negative shift from normal cognitive aging toward AD pathophysiology (Aim 3). Specific innovations (in addition to the DO mice) include the use of multi-scale network methods to identify resilience proteins that are capable of distinguishing perturbations and networks that initiate cognitive resilience from those that merely correlate; our cross-species translational platform for testing candidates identified in mice in multiple human cohorts; the unmatched mouse resources and expertise of The Jackson Laboratory, which will be leveraged for gene validation and creation of precision AD models; and our team of experts in human and mouse genetics, bioinformatics, high-resolution microscopy and functional validation. IMPACT: We will discover and validate targets for promoting healthy brain aging and resilience to AD and will provide mechanistic insight into cognitive resilience. The identification of genetic factors and mechanisms underlying variation in normal cognitive aging, and that lead to pathologic brain aging, will likely point to novel therapeutic strategies, including ones that may be used before the onset of AD symptoms.